The creation and testing of a fully continuous tubular crystallization device suited for incorporation into flow chemistry setups

Abstract

The study presents the use of a continuous crystallization device that can be directly incorporated into flow chemistry setups. Inside this device spontaneous nucleation and growth of organic molecules are controlled and maintained, using Aspirin as model molecule. The identification of the optimal crystallization scenario is discussed in view of the chemical stability of Aspirin and based on the determination of the solubility and the metastable zone width corresponding to the presented experimental setups. Physicochemical analyses combined with heat transfer modeling of the solution whilst flowing through a capillary placed inside a thermostated water bath provide the desired cooling profile and hence the degree of supersaturation along the system. The crystalline quality and stability of the crystalline output is evidenced for two different pump setups having distinguished flow patterns to show the independence on the flow stability, an important parameter for the success rate of the complete reaction scheme and in the perspective of operation scale-up. Reproducible output of material with narrow size distributions is obtained throughout all experiments.

On the effect of flow restrictions on the nucleation behavior of molecules in tubular flow Nucleators

“…T 0 for Brivaracetam was 45°C [22], the T 0 for Aspirin was set at 65°C. [24] Therefore, the gap between T 0 and T N is 35 for Brivaracetam and 55°C for Aspirin. Using Eq.…”

“…Putting more restrictions with Fig. 3 Solubility diagrams of Brivaracetam [22] (left) and Aspirin [24] (right) and indicated supersaturated σ exp for crystallization tests and metastable zonewidth σ MSZW at identical nucleation temperature T N of 10°C Fig. 4 Drawing of two constrictions and expansions inside the flow path.…”

“…with v the flow velocity in m/s, L the characteristic length, in this case the tube diameter in m, ρ the fluid density in kg/m 3 and μ the dynamic viscosity of the liquid in Pa.s. The used values for Re calculation for the current set of parameters were obtained previously [24]. The step height h is calculated by…”

“…After the exit of the growing nuclei out of the reactor further crystal growth is reported to be conducted in storage vessels, tubing, or directly casted on filters, both for direct nucleation in one single solvent or by addition of antisolvent. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25].…”

“…[22] As a consequence, the size of the crystalline material obtained afterwards results directly from the ruling elevated nucleation rates. [24,25].…”